CN1133426C - Novel stable preparation use paracetamol as base and method for preparing same - Google Patents

Novel stable preparation use paracetamol as base and method for preparing same Download PDF

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Publication number
CN1133426C
CN1133426C CNB971913714A CN97191371A CN1133426C CN 1133426 C CN1133426 C CN 1133426C CN B971913714 A CNB971913714 A CN B971913714A CN 97191371 A CN97191371 A CN 97191371A CN 1133426 C CN1133426 C CN 1133426C
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pounce
breath
liquid preparation
acetaminophen
solution
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CN1204960A (en
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F·迪特林
D·弗雷
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SCR Pharmatop
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Abstract

Novel stable paracetamol compositions for use in therapeutic chemistry and specifically galenic pharmacy are disclosed. The compositions contain a solution of paracetamol in an aqueous solvent combined with a buffer having a pH of 4 to 8, and a free radical capturing agent. A water-insoluble inert gas is carefully bubbled through the aqueous solvent to remove oxygen from the medium. Said compositions may also be combined with a centrally or peripherally acting analgesic agent, and are provided as injectable compositions for relieving pain.

Description

New stable preparation based on acetaminophen and preparation method thereof
The present invention relates to new stable liquid analgetic preparation, said preparation contains acetaminophen as main component, can combine with the pain relieving derivant or not combine with the pain relieving derivant.
Known for many years, acetaminophen is in wet environment, particularly in aqueous solution, can hydrolysis produce p-aminophenol, itself then decomposes generation quinone-imines this chemical compound, and this is at the paper of FAI RBROTHER J.E.: acetaminophen (Analytical Profi1es ofDrug Sub stances (1974), the 3rd the volume, the 1-109 page or leaf) in mention.In case the decomposition rate of acetaminophen is along with the increase of temperature and meet light then strengthen.
In addition, extensively describe for the unstability (because due to pH of solution) of acetaminophen in aqueous solution is existing.Therefore; according to being entitled as " stability of N-acetyl group-p-aminophenol aqueous solution " (KOSHY K.T. and LACH J.I.J.Pharm.Sci., 50 (1961), 113-118 page or leaf) literary composition; acetaminophen is unsettled in aqueous solution, and this is mainly relevant with hydrolysis under acid and alkaline environment.When pH value this catabolic process minimum near 6 time, half-life of 25 ℃ of product degradation up to 21.8.
According to Arrhenius formula (Arrhenius) and the known concrete reaction constant of measuring by these authors, be expected to be 19 months 25 ℃ of acetaminophen concentration of aqueous solution 5% required times that descended of storing with optimum pH.Except that hydrolysis, the acetaminophen molecule also carries out another kind and decomposes, comprises formation quinone-imines, and polymerization takes place the latter easily, forms polymer with nitrogen.
To existing description of toxic metabolite that these polymer and particularly those products that produced by N-acetyl group-p-aminophenol are acetaminophen, this just makes it have significant cytotoxicity and haemolysis.The decomposition of this metabolite in water-bearing media is more complicated, and generate 1,4-benzoquinone and hydroquinone (D.DAHLIN, J.Med.Chem., 25 (1982), 885-886).
In view of the present situation in this field and consider quality control requirement concrete concerning the medicine practice rule, the stability of acetaminophen in aqueous solution is not enough, thereby can not be prepared into the injection liquid pharmaceutical composition.Therefore, successfully not develop with the acetaminophen as yet at present be active component, through the liquid pharmaceutical formulation of parenterai administration.
In order to slow down the decomposition of acetaminophen in aqueous solution, carried out big quantity research.Be entitled as " Stabilization by ethylenediamine tetraacetic acid ofamide and other groups in drug compound " (FOGG Q.G. and SUMMAN, A.M., J.Clin.Pharm.Ther., 17:(1992), address in article 107-109): through after the storage in 120 days, wherein the content of the p-aminophenol that is obtained by the acetaminophen hydrolysis is 19.8% of acetaminophen initial concentration to 0.1% acetaminophen aqueous solution under dark surrounds.The EDTA of interpolation 0.0075% makes resolution ratio be reduced to 7%.On the other hand, having or do not having in the presence of the 1000ppm ascorbic acid, the aqueous slkali of distillation acetaminophen obtains 14% ammonia concentration.Because the character of himself, in fact ascorbic acid is very suitable for this Stabilization.Yet in case contact with high light, the acetaminophen solution that contains the 1000ppm ascorbic acid will produce 98% ammonia.On the contrary, add EDTA (0.0075%) and can cut down resolution ratio in this solution, the productive rate of ammonia is not more than 14%.
However make great efforts, still can not prepare aqueous solution, particularly injection solution with acetaminophen of guaranteeing stability.
The objective of the invention is to solve by rights the problems referred to above satisfactorily.The present invention relates to wherein adding stable acetaminophen pharmaceutical composition free-radical antagonists, in aqueous solvent.This aqueous solvent can be the aqueous mixture of water or moisture and polyol compound (for example Polyethylene Glycol (PEG) 300,400,1000,1540,4000 or 8000, propylene glycol or tetraethylene glycol (TEG)).Also can use water-soluble alcohol such as ethanol.
The stability of above-mentioned aqueous solution not only depends on the selection of described carrier, also depends on other variable factors, for example carefully regulates pH, removes the oxygen that is dissolved in the carrier and adds free-radical antagonists or free radical scavenger.
By bubbling charge into noble gas, preferred nitrogen can easily be removed dissolved oxygen.
Suitable free-radical antagonists is selected from ascorbic acid derivates, has those derivants and the straight chain or the cyclopolyol chemical compound of at least one thiol functional group.
Even being D-or L-ascorbic acid, the alkali metal salt of ascorbic acid, the alkali salt of ascorbic acid, preferred ascorbic acid derivates dissolves in the acid ascorbyl ester of water-bearing media.
Have the aliphatic organic compound that the free radical scavenger of thiol functional group can be replaced by one or more thiol, for example cysteine, acetylcysteine, TGA and salt thereof, thiolactic acid and salt thereof, dithiothreitol, DTT, reduced glutathione, thiourea, thioglycerin, methionine and sulfydryl ethyl sulfonic acid.
As the preferred straight chain of polyhydric alcohol or the cyclopolyol of free radical scavenger, for example mannitol, sorbitol, inositol, isosorbide, glycerol, glucose and propylene glycol.
In stablizing the required free radical scavenger of acetaminophen, ascorbic acid derivates is preferably sodium ascorbate usually.The derivant that preferred thiol replaces is cysteine, the glutathion of going back ortho states, N-acetylcystein and sulfydryl ethyl sulfonic acid.
Several free radical scavengers are used in combination to be proved to be may be favourable, as long as they are water-soluble and compatible with each other.Chang Yong free radical scavenger is mannitol, glucose, sorbitol or glycerol especially.They easily can be used in combination.
Adding one or more chelating agen in preparation may be favourable with the stability of improving molecule, because active component is responsive for existing trace metal, trace metal can quicken its decline.
Chelating agen is for example nitrilotriacetic acid(NTA), ethylenediaminetetraacetic acid, ethylenediamine N, N '-oxalic acid-N, N '-dipropionic acid, ethylenediamine tetraacetic phosphoric acid, 2,2 '-(ethylenediamine) two butanoic acid or ethylene glycol bisthioglycolate (diamino ethyl ether) N, N, N ', N '-tetraacethyl and sodium salt thereof or calcium salt.
The effect of chelating agen also is to cooperate with existing divalent ion (copper, zinc, cadmium), and these divalent ions are to the negative effect that worn out of preparation after storing.
The bubbling feeding can be nitrogen or carbon dioxide or other noble gases with the gas of driveing oxygen in solution.Preferred nitrogen.
The isotonicity of preparation can be by adding appropriate amount sodium chloride, glucose, levulose or potassium chloride or calcium chloride or gluconic acid calcium glucoheptonate or its mixture be achieved.Preferred isotonic agent is a sodium chloride.
Used buffer agent is to be applicable to that the people injects the buffer agent of dispenser, and its pH value can be adjusted to 4-8.Preferred reducing agents is based on the acetate of alkali metal or alkaline-earth metal or phosphate.Preferred buffer agent is the sodium acetate/dibastic sodium phosphate that is adjusted to required pH with hydrochloric acid or sodium hydroxide.The concentration of this buffer agent can be the 0.1-10 mg/ml.Preferred concentration range is the 0.25-5 mg/ml.
On the other hand, injection preparation must be aseptic, and is suitable for through heat treated sterilization.Known antioxidant under certain conditions is glutathion destroyed [FIALAIRE A. etc., J.Pharm.Biomed.Anal., the 10th volume, No. 6,457-460 page or leaf (1992)] for example.According to the difference of the temperature that is adopted, the destructive rate of reproducibility glutathione can be 40-77% in the heat sterilization operation.In this sterilizing methods, use can keep the method for these antioxidant integrity usually.In aqueous solution, add chelating agen and can suppress for example thermal decomposition of glutathion of sulfur hydroxy derivative.
Composition of liquid medicine of the present invention is preferably the compositions of injection.If so-called weak solution the solution of venoclysis (promptly can be directly by), then the content of acetaminophen can be 2 mg/ml to 50 mg/ml in the solution, if so-called concentrated solution is (promptly by vein or intramuscular approach direct injection, perhaps dilution earlier, the solution of infusion slowly then), then the content of acetaminophen can be 60 mg/ml to 350 mg/ml in the solution.The preferred concentration of weak solution is the 5-20 mg/ml, and the preferred concentration of concentrated solution is the 100-250 mg/ml.
Pharmaceutical composition of the present invention can also contain the another kind of active component of strengthening the acetaminophen specific function.
Especially, pharmaceutical composition of the present invention can contain the analgesic that acts on CNS, for example the morphine analgesic.
The morphine analgesic is selected from natural, semi-synthetic or synthetic morphine derivatives and piperidine derivative, they are selected from following medicine, and these medicines are not to be exhaustive: uncle's fourth coffee, Ciramadol, codeine, diffusing pain, Propoxyphene, dihydrocodeinone, Dilauid, cetobemidone, levothyl, levorphan, Meptazinol, methadone, morphine, nalbuphine, gewalan, dizocine, diacetylmorphine, paracodin, Dipipanone, methorphan, dextro-methorphan.
Preferred morphine derivatives is codeine sulfate or morphine hydrochloride.
The concentration that with the codeine is the codeine of basic representation or codeine derivant is 0.2%-25% with respect to the content of acetaminophen.Preferred codeine derivant is a codeine sulfate.Its concentration is 0.5-15% with respect to the content of acetaminophen.
The concentration that with the morphine is the morphine of basic representation or morphine derivatives is 0.05%-5% with respect to the content of acetaminophen.Preferred morphine derivatives is a morphine hydrochloride.Its concentration is preferably 0.5-15% with respect to the content of acetaminophen.
Can also in the present composition, add antibiotic medicine for example AINS class antibiotic medicine, particularly phenylacetic acid compound.Described medicine is for example ketoprofen, flurbiprofen, Artiflam, actol, diclofenac or naproxen.
In addition, can in the present composition, mix Bendectin, described Bendectin or the Antipsychotic drug that acts on CNS be haloperidol or chlorpromazine or metopimazine for example, and perhaps for example metoclopramide or domperidone of gastric motility mediation class medicine is even 5-hydroxy tryptamine can medicine.
Can also in the present composition, mix town's epilepsy medicine for example sodium valproate, clonazepam, carbamazepine or phenytoin.
Also acetaminophen can be combined with corticosteroid, described corticosteroid is for example meticorten, meticortelone, methyl meticorten, dexamethasone, betamethasone or its ester.
Can also for example amitriptyline, imipramine, Clomipramine combine with tricyclics with acetaminophen.
Can contain 0.100-0.500 gram antibiotic medicine in per 1000 milliliters of preparations.
Concentrated solution
The water content of representing with percent preferably accounts for more than 5% of cumulative volume, more preferably 10-65%.
The percentage composition of propylene glycol is preferably greater than 5%, more preferably 20-50%.
Used PEG is preferably PEG 300, PEG 400, PEG 1000, PEG 1540 or PEG 4000.Used concentration is 10-60% (weight).PEG 300 and PEG 400 are particularly preferred.Preferred concentration range is 20-60%.
The concentration of ethanol scope is the 0-30% that accounts for cumulative volume, is preferably 0-20%.
The concentration of used tetraethylene glycol (TEG) is no more than 15%, makes to use maximum through parenteral route every day, i.e. 0.7 milliliter/kg body weight.
According to route of administration, the concentration of glycerol can change between 0.5-5%, with regulate the viscosity of suitable substrate.
Weak solution
The water content of representing with percent accounts for more than 20% of cumulative volume, is preferably 25-100%.
The percentage composition of propylene glycol preferably is preferably 0-10%.
Used PEG is preferably PEG 300, PEG 400 or PEG 4000.PEG4000 most preferably.Preferred concentration range is 0-10%.The concentration of used tetraethylene glycol (TEG) is no more than 5%, is preferably 0-4%.
The concentration of used ascorbic acid or ascorbic acid derivates is preferably greater than 0.05 mg/ml, more preferably 0.15 mg/ml to 5 mg/ml.As long as be no more than solubility limit, in fact can use higher amount.Ascorbic acid or the ascorbic acid derivates of using higher concentration to the people can reach prevention or therapeutic purposes.
For weak solution, the concentration of sulfur hydroxy derivative is 0.001% to 30%, more preferably 0.005% to 0.5%, and for concentrated solution, the concentration of sulfur hydroxy derivative is 0.1% to 20%.
Preferably the pH value of solution is adjusted to acetaminophen the most stable value in aqueous solution, promptly pH is about 6.0.
The compositions of preparation like this can be packaged in the sealed glass bottle, or in the vial or the bottle with polymeric material such as polyethylene manufacturing of being with stopper of packing into, or pack into and use in the soft bag of polyethylene, polrvinyl chloride or polypropylene manufacturing.
Compositions can be passed through heat sterilization, for example 121 ℃ of heating 20 minutes, perhaps sterilizes through aseptic filtration.
The usually preferred present composition has following composition:
Concentrated solution
Composition The injection (every milliliter) that only contains acetaminophen With the bonded Tylenol injection of morphine compounds (every milliliter)
Codeine Morphine
Acetaminophen 0.160 gram 0.160 gram 0.160 gram
Codeine sulfate 3H 2O - 0.0036 gram -
Morphine hydrochloride 3H 2O - - 0.00037
Propylene glycol 0.270 milliliter 0.270 milliliter 0.270 milliliter
PEG?400 0.360 milliliter 0.360 milliliter 0.360 milliliter
Sodium acetate 0.002 gram 0.002 gram 0.002 gram
Reduced glutathione 0.002 gram 0.002 gram 0.002 gram
Hydrochloric acid 1N In right amount to pH6.0* In right amount to pH6.0* In right amount to pH6.0*
Water for injection In right amount to 1000 milliliters In right amount to 1000 milliliters In right amount to 1000 milliliters
Nitrogen An amount of bubbling An amount of bubbling An amount of bubbling
* above-mentioned pH makes the actual pH that records with pH meter after 5 times the diluent with distilled water.Apparent pH that it should be noted that pure solution is different.
The solution that the solvent mixture that use is made up of 30% propylene glycol, 40% PEG400 and 30% water constitutes (No. 20 solution) can dissolve about 200 mg/ml acetaminophen at 20 ℃.Select the concentration of 160 mg/ml, can guarantee not occur tangible recrystallize phenomenon at low temperatures.Under this situation, 6.25 milliliters of described solution contain 1000 milligrams of acetaminophen.
Weak solution
Composition The injection (every milliliter) that only contains acetaminophen With the bonded acetaminophen solution of codeine (every milliliter)
The morphine compounds is a codeine The morphine compounds is a morphine
Acetaminophen 0.0125 gram 0.125 gram 0.125 gram
Codeine sulfate 3H 2O - 0.00018 gram -
Morphine hydrochloride 3H 2O - - 0.000019 gram
Mannitol 0.025 gram 0.025 gram 0.025 gram
The dibastic sodium phosphate dihydrate 0.00025 gram 0.00025 gram 0.00025 gram
Sodium chloride 0.002 gram 0.002 gram 0.002 gram
Disodiumedetate 0.0001 gram 0.0001 gram 0.0001 gram
Hydrochloric acid or sodium hydroxide In right amount to pH5.5 In right amount to pH5.5 In right amount to pH5.5
Water for injection In right amount to 1000 milliliters In right amount to 1000 milliliters In right amount to 1000 milliliters
Nitrogen An amount of bubbling An amount of bubbling An amount of bubbling
The present composition is as the alleviating pain medicine.For lighter pain, this solution only contains acetaminophen.For acute pain, this solution also contains the morphine analgesic.In addition, acetaminophen solution also has antipyretic effect.
Provide the following example and describe, and unrestricted the present invention.
Embodiment 1
The mensuration of optimum solvent mixture
1.1 concentrated solution
In solvent mixture, increase the amount of acetaminophen gradually.The dissolution velocity of acetaminophen increases along with the rising of temperature, therefore by solvent mixture being heated to 60 ℃, carries out solubility experiment in each medium.In order to estimate dissolubility fully, each solution was stored 72 hours at 25 ℃ or 4 ℃.
During solubility values is listed in the table below:
The experiment sequence number Water (ml) Polypropylene glycol (ml) ?PEG?400 ?(ml) Ethanol Tetraethylene glycol (TEG) (ml) Dissolubility in the time of+4 ℃ (mg/ml) Dissolubility in the time of+25 ℃ (mg/ml)
1 ?0.3 ?0.4 ?0.3 - - ?110 ?130
2 ?0.4 ?0.3 ?0.3 - - ?110 ?130
3 ?0.15 ?0.3 ?0.4 - 0.15 ?190 ?230
4 ?0.5 ?- ?0.5 - - ?110 ?150
5 ?0.4 ?0.3 ?0.2 0.1 - ?＜110 ?120
6 ?0.5 ?0.3 ?0.1 0.1 - ?＜100 ?130
7 ?0.4 ?0.4 ?0.1 0.1 - ?＜100 ?150
8 ?0.5 ?0.3 ?0.2 - - ?＜100 ?120
9 ?0.6 ?0.3 ?0.2 - - ?＜100 ?＜100
10 ?0.5 ?0.4 ?0.1 - - ?＜100 ?＜100
11 ?0.55 ?0.3 ?0.05 0.1 - ?＜100 ?＜100
12 ?0.45 ?0.4 ?0.05 0.1 - ?＜100 ?120
13 ?0.65 ?0.3 ?0.05 - - ?＜100 ?＜100
14 ?0.55 ?0.3 ?0.05 - - ?＜100 ?＜100
15 ?0.4 ?0.4 ?0.2 - - ?＜100 ?＜150
16 ?0.45 ?0.45 ?0.1 - - ?＜100 ?＜110
17 ?0.4 ?0.2 ?0.4 - - ?160 ?200
18 ?0.5 ?0.2 ?0.3 - - ?160 ?160
19 ?0.5 ?0.1 ?0.3 - - ?100 ?190
20 ?0.3 ?0.3 ?0.4 - - ?190 ?200
21 ?0.3 ?0.2 ?0.35 - 0.15 ?160 ?210
22 ?0.25 ?0.25 ?0.35 - 0.15 ?170 ?220
The solubility values of solvent mixture does not increase in the same way with the increase of temperature.If adding ethanol, dissolubility can not increase.
In addition, owing at this solution, particularly containing the supersaturation that occurs in the medium of PEG, the recrystallize phenomenon that postpones after cooling, occurs.Under these conditions, the solution of being studied was stored 14 days, crystalline solution and acetaminophen crystal seed behind this interval, are not occurred to wherein adding then, to cause potential supersaturated solution crystallization at 20 ℃.Find that at last the dissolubility of acetaminophen is the highest in No. 20 and No. 3 solution, varies with temperature, its threshold value is the 160-170 mg/ml.
1.2 weak solution
In being heated to 30 ℃ solvent mixture in advance, add the acetaminophen that exceeds the solubility threshold amount fully.Stir and after 20 ℃ of coolings, should molten filtration.By reading the absorbance of 1: 200 times of dilution filtrate, measure the acetaminophen content of these solution at 240nm.Outcome record is in following table.
Solution type (except as otherwise noted, primary solvent is a distilled water) The concentration of acetaminophen (milligram/50 milliliters)
Water 720
5% glucose 710
4.82% levulose 730
7% mannitol 680
5% sorbitol 685
0.9% sodium chloride 615
10% gluconic acid glucose enanthic acid calcium 670
Lestradet ' s solution (5% glucose, 0.2% sodium chloride, 0.15 % potassium chloride, 1.1% gluconic acid glucose enanthic acid calcium) 730
Ringer ' s solution (0.7% sodium chloride, 0.1% potassium chloride, 0.1 % sodium chloride)? 730
Ringer ' s phosphoric acid solution (0.7% sodium chloride, 0.182% monopotassium phosphate, 0.182% calcium chloride) 710
Ringer ' s acetic acid solution (0.7% sodium chloride, 0.131% potassium acetate, 0.013% calcium chloride) 715
Carbamide 0.3M 725
Solution type (using the following solution of Ringer ' s formulations prepared from solutions) The concentration of acetaminophen (milligram/50 milliliters)
Pure Ringer ' s solution 735
4.0%PEG 4000+1.0% propylene glycol+0.5% ethanol 905
4.0%PEG 4000+1.0% propylene glycol+1.0% ethanol 905
4.0%PEG 4000+1.0% propylene glycol+2.0% ethanol 930
Solution type (preparing following solution) with 0.9% sodium chloride solution The concentration of acetaminophen (milligram/50 milliliters)
0.9% sodium chloride solution 615
+ 0.6% tetraethylene glycol (TEG) 640
+ 1.2% tetraethylene glycol (TEG) 680
+ 3.0% tetraethylene glycol (TEG) 720
1.0％PEG?4000 630
1.0%PEG 4000+0.6% tetraethylene glycol (TEG) 660
1.0%PEG 4000+1.2% tetraethylene glycol (TEG) 710
3.0%PEG 4000+2.0% tetraethylene glycol (TEG) 950
The dissolubility of acetaminophen increases because of the existence of PEG.
With the temperature is function, measures the situation of concentration range in the solubility with temperature variation of acetaminophen in PEG 4000 and 0.9% sodium chloride solution of 0-7% in distilled water.
The result is as shown in the table:
1000 milligrams of solvent volume (milliliter) that acetaminophen is required of dissolving under the different temperatures
The concentration of PEG 4000 (%/volume) in 0.9% sodium chloride solution 4℃ 17℃ 22℃ 30℃ 42℃
0％ 100 92 80 65 42
1％ 99 78 67 63 47
2％ 91 72 63 59 45
3％ 80 64 56 54 41
4％ 82 62 57 49 36
5％ 79 59 51 46 34
7％ 78 61 48 42 30
4.1 concentrated solution
Consumption
Composition Do not fill the solution of nitrogen Bubbling fills the solution of nitrogen
Acetaminophen 0.160 gram 0.160 gram
Propylene glycol 0.270 milliliter 0.270 milliliter
PEG?400 0.360 milliliter 0.360 milliliter
Sodium hydroxide or hydrochloric acid 1N In right amount to pH6.0 In right amount to pH6.0
Nitrogen Do not have Purge in right amount and charge into
Water for injection In right amount to 1000 milliliters In right amount to 1000 milliliters
Is that No. 20 solution of 160 mg/ml are adjusted to pH6.0 with sodium hydroxide or 1N hydrochloric acid with acetaminophen concentration, to wherein charging into or inflated with nitrogen not.Under blanket of nitrogen or in air,, will be packaged in autoclave and to jump a queue and add 10 milliliters of these solution sterilizations 20 minutes in the bottle of medicated cap sealing at 121 ℃.Adopt liquid chromatograph to measure the percent at acetaminophen main peak second peak then, and adopt absorptiometry,, measure pink intensity by in peak absorbing wavelength-be that the 500nm place reads this solution.
The result
Experimental solutions Acetaminophen second peak accounts for the percent (%) of main peak Solution is at the absorbance at 500nm place
Do not fill the autoclave sterile solution of packing under the nitrogen condition 0.054 0.08
The autoclave sterile solution of under condition of nitrogen gas, packing 0.036 0.03
This shows that the solution aberration of packing is very tangible under blanket of nitrogen.
For detect 0% and 1%PEG-acetaminophen solution under the cooling preservation, keep clarification, prepare following solution:
Composition The solution that does not contain PEG Be added with the solution of PEG
Acetaminophen 1 gram 1 gram
PEG?4000 - 1 gram
The aqueous solution for injection of 0.9% sodium chloride In right amount to 125 milliliters In right amount to 100 milliliters
After 10 days, there is not an experiment bottle crystallization to occur these solution storages at 4 ℃.Therefore, if this solution keeps clarification in the interval of research, the existence of PEG then is not enforceable.
Example II
To the research that experimentizes of acetaminophen ruined characteristic in solution
2.1 the proof acetaminophen is unstable in solution
In case the acetaminophen in water or No. 20 solution is met light or high temperature storage then is shown as pink colour rapidly.At 50 ℃, change color takes place in 2 weeks.The appearance of this color is relevant in the increase that the 500nm wavelength peak absorbs with solution.According to the article of above mentioned Fairbrother, acetaminophen contacts with wet environment and can cause hydrolysis to form p-aminophenol, and is oxidized then, pink colour occurs, generates quinone-imines usually.
2.2 the evaluation of acetaminophen catabolite
In the solution of water or part water, in storage process, do not detect p-aminophenol.Coloured product of pink colour produces rapidly, and product is the function of temperature and light.As time goes on, the color of this derivant obviously deepens, and becomes brown.
If above-mentioned all situations takes place, so with document in report form contrast, the destruction of acetaminophen at first relates to oxidizing process, is hydrolysis then.According to this theory, the oxidant that exists in acetaminophen and the water, the oxygen that for example is dissolved in the water layer react.This mechanism relates to the generation of the free radical that causes the molecule coupling, and this is owing to make color become the result that brown coloured derivant produces by pink colour.
2.3 proof suppresses the experiment of free-radical generating
The type reaction that produces free radical comprises and adds 30% aqueous hydrogen peroxide solution and concentration is five hydration copper of 62.5 mg/ml in the aqueous solution of 1.25% acetaminophen.Color reaction took place after a few minutes, caused color to become dark-brown by yellow.If add free radical scavenger or glycerol in advance in acetaminophen solution, then color depth shoals.Color depth changes with the type of adding free radical scavenger, is passed judgment on by color depth, and color is shallow as follows successively by being deep to:
Only contain acetaminophen＞acetaminophen+N-acetylcystein＞acetaminophen+cysteine＞acetaminophen+sorbitol＞acetaminophen+mannitol＞acetaminophen+glycerol.
EXAMPLE III
By selecting to make the most stable DH of acetaminophen stablize acetaminophen solution
3.1 concentrated solution
Experimental solutions
Composition Consumption
Acetaminophen 0.160 gram
Propylene glycol 0.270 milliliter
PEG?400 0.360 milliliter
Sodium hydroxide 1N or hydrochloric acid 1N are an amount of PH7.0-8.0-9.0-9.5-10.0 is corresponding with actual pH: pH5.8-6.7-7.1-7.5-8.0-8.5
Nitrogen is an amount of Purge and charge into
Water for injection In right amount to 1000 milliliters
To contain concentration with sodium hydroxide or ordinary salt acid solution is that the solution 20 of 160 mg/ml acetaminophen is adjusted to different pH: the actual pH after given apparent pH and the 5 times of dilutions (in the bracket) is compared: 7.0 (5.8)-8.0 (6.7)-8.5 (7.1)-9.0 (7.5)-9.5 (8.0)-10.0 (8.5).The bottle that will load 10 milliliters of described solution under blanket of nitrogen is jumped a queue and is added the medicated cap sealing, 121 ℃, in autoclave with its sterilization 20 minutes, then each bottle was placed 72 hours in 105 ℃ in dark surrounds, perhaps 5000 ° of K and 25 ℃ with photochemical rayed 264 hours.
The result
After the autoclave sterilization, only there is the solution that is adjusted to pH10 to demonstrate pink colour.105 ℃ store 72 hours after, at pH7.5-9.5, the concentration minimum of the absorbance at 500nm place and acetaminophen catabolite.If store under illumination, then along with pH value increases, color depth is also strengthened.When pH7.0 (actual pH is 5.8), change color extremely a little less than.No matter be acetaminophen content, or catabolite all is not subjected to the influence of pH value.
3.2 weak solution
Experimental solutions
Composition Consumption
Acetaminophen 0.008 gram
Sodium chloride 0.0067 gram
The disodium hydrogen phosphate dihydrate 0.0012 gram
5% citric acid is an amount of pH5.0-6.0-7.0
Nitrogen is an amount of Purge and charge into
Water for injection In right amount to 1000 milliliters
To contain dilution and the buffered aqueous solution that concentration is 8 mg/ml acetaminophen with citric acid solution and be adjusted to different pH value: pH5.0-7.0.
The bottle that will load 10 milliliters of described solution under blanket of nitrogen is jumped a queue and is added the medicated cap sealing, 121 ℃, in autoclave with its sterilization 20 minutes, then each bottle was placed 231 hours in 70 ℃ in dark surrounds.
The result
After the autoclave sterilization, only there is the solution that is adjusted to pH7 to demonstrate pink colour.After the storage, this solution is shown as the most bright-coloured pink colour.When pH6.5-5.0, the change color of solution weakens.
EXAMPLE IV
Make acetaminophen stable in solution by blasting nitrogen except that deoxidation
4.2 weak solution
Experimental solutions
Composition Consumption
Do not fill the solution of nitrogen Bubbling fills the solution of nitrogen
Acetaminophen 0.008 gram 0.008 gram
Sodium chloride 0.008 gram 0.008 gram
The disodium hydrogen phosphate dihydrate 0.001 gram 0.001 gram
5% citric acid In right amount to pH6.0 In right amount to pH6.0
Nitrogen Do not have Purge in right amount and charge into
Water for injection In right amount to 1000 milliliters In right amount to 1000 milliliters
The dilute aqueous solution that will contain acetaminophen with citric acid solution is adjusted to pH6.0.
The bottle that will load 10 milliliters of described solution under blanket of nitrogen is jumped a queue and is added the medicated cap sealing, stores 15 hours in 98 ℃ thermophore then.
Adopt liquid chromatograph to measure the percent at acetaminophen main peak second peak then, and adopt absorptiometry,, measure pink intensity by in peak absorbing wavelength-be that the 500nm place reads this solution.
The result
Experimental solutions Acetaminophen second peak accounts for the percentage ratio (%) of main peak Solution is at the absorbance at 500nm place
Do not fill the solution of packing under the nitrogen condition 1.57 0.036
The solution of under condition of nitrogen gas, packing 0.44 0.0016
The pink colour of the solution of packing under blanket of nitrogen is more weak than the pink colour of not filling the solution that the solution packed under the nitrogen condition obtains after sterilization under the blanket of nitrogen.
EXAMPLE V
Make acetaminophen solution-stabilized by adding free-radical antagonists
5.1 concentrated solution
Composition Consumption
Acetaminophen 0.160 gram
Propylene glycol 0.270 milliliter
PEG?400 0.360 milliliter
Sodium hydroxide 1N or hydrochloric acid 1N are an amount of pH6.0
Free radical scavenger (referring to quantitative result) (referring to quantitative result) in right amount
Nitrogen is an amount of Purge and charge into
Water for injection In right amount to 1000 milliliters
Gained solution is divided in the bottle of 10 milliliters of capacity, jumps a queue and the aluminum medicated cap adds medicated cap with the brombutyl stopper.121 ℃, sterilization after 20 minutes in autoclave, each bottle under the condition that room temperature and 5500 ° of K actinic lights exist, was perhaps stored 48 hours under 70 ℃ and dark condition.Measure any change color of preparation.
The result
Free radical scavenger Concentration The appearance color degree of depth of solution behind the chance light The appearance color degree of depth at 70 ℃ of solution
No scavenger - Pink colour (+) Pink colour (++)
Sodium sulfite 0.295 mg/ml Colourless Colourless
Sodium ascorbate 1.0 mg/ml Yellow (+) Yellow (+)
Reduced glutathione 1 mg/ml Colourless Colourless
Reduced glutathione 8 mg/ml Colourless Colourless
Cysteine hydrochloride 1 mg/ml Cotton-shaped Cotton-shaped
α-monothioglycerol 1 mg/ml Colourless Colourless
Dithiothreitol, DTT 1 mg/ml Colourless Colourless
Mannitol 50 mg/ml Colourless Colourless
5.2 weak solution
Experimental solutions
Composition Consumption
Preparation A Preparation B Formulation C
Acetaminophen 0.008 0.01 0.0125
Sodium chloride 0.008 0.008 0.00486
The disodium hydrogen phosphate dihydrate 0.001 0.001 0.00125
Hydrochloric acid In right amount to pH6.0 In right amount to pH6.0 In right amount to pH6.0
C.R.L. (referring to quantitative result) in right amount
Nitrogen is an amount of Purge and charge into
Water In right amount to 1000 milliliters
Prepared solution is divided in the bottle of 10 milliliters, 100 milliliters or 80 milliliters capacity, jumps a queue and the aluminum medicated cap adds medicated cap with the brombutyl stopper.Measure any change color of preparation.
121 ℃, sterilization after 20 minutes in autoclave, each bottle under the condition that room temperature and 5500 ° of K actinic lights exist, is perhaps stored 48 hours (preparation A) under 70 ℃ and dark condition.
124 ℃, in autoclave the sterilization 7 minutes after, with each bottle in dark surrounds in room temperature storage 48 hours (preparation B and C).Measure the pink colour migration and the acetaminophen of preparation, and if use sulfur hydroxy derivative also to measure CRL.
Result's (CRL=free radical scavenger)
Used C.R.L. Concentration The outward appearance of solution behind the chance light Outward appearance at 70 ℃ of solution
Color The degree of depth Color The degree of depth
No C.R.L. - Pink colour (+) Pink colour (++)
Thiourea 0.5 mg/ml Colourless Colourless
Dithiothreitol, DTT 1 mg/ml Colourless Colourless
α-monothioglycerol 1 mg/ml Colourless Colourless
Glutathione 1 mg/ml Colourless Colourless
Sodium ascorbate 0.2 mg/ml Pink colour (+) Pink colour (+)
0.4 mg/ml Colourless Yellow (+)
0.6 mg/ml Pink colour (+) Yellow (+)
1.0 mg/ml Colourless Yellow (+)
Cysteine hydrochloride 0.05 mg/ml Colourless Colourless
0.1 mg/ml Colourless Colourless
0.25 mg/ml Colourless Colourless
0.5 mg/ml Colourless Colourless
0.75 mg/ml Colourless Colourless
1 mg/ml Colourless Colourless
2 mg/ml Colourless Colourless
5 mg/ml Colourless Colourless
Used C.R.L. Concentration The outward appearance of solution Dosage (% of theoretical value)
Color The degree of depth C.R.L. Acetaminophen
The cysteine hydrochloride monohydrate 0.2 mg/ml Colourless 80％ 99.2％
The cysteine hydrochloride monohydrate 0.5 mg/ml Colourless 95％ 99.6％
N-acetylcystein 0.2 mg/ml Colourless 88％ 99.2％
Mannitol 20 mg/ml Colourless
Mannitol 40 mg/ml Colourless
Mannitol 50 mg/ml Colourless
Glucose 50 mg/ml Colourless
Example VI
By adding the stable acetaminophen solution that contains morphine compounds of free radical scavenger
6.1 concentrated solution
Experimental solutions
Composition Consumption
Acetaminophen 0.160 gram
Codeine phosphate 0.008 gram
Propylene glycol 0.270 milliliter
PEG?400 0.360 milliliter
Hydrochloric acid 1N is an amount of In right amount to pH6.0
Free radical scavenger (referring to quantitative result) in right amount
Water for injection In right amount to 1000 milliliters
Gained solution is divided in the bottle of 10 milliliters of capacity, jumps a queue and the aluminum medicated cap adds medicated cap with the brombutyl stopper.121 ℃, sterilization after 20 minutes in autoclave, with each bottle under the condition that room temperature and 5500 ° of K actinic lights exist, perhaps storage 48 hours under dark and 70 ℃ condition.Measure any change color of preparation.
The result
Used free radical scavenger Concentration The outward appearance of solution behind the chance light Outward appearance at 70 ℃ of solution
Color The degree of depth Color The degree of depth
No free radical scavenger - Pink colour (+) Pink colour (++)
Sodium sulfite 0.295 mg/ml Yellow (+) Yellow (++)
Sodium ascorbate 1.0 mg/ml Yellow (++) Yellow (+++)
Reduced glutathione 1 mg/ml Yellow (+) Yellowish-brown (+++)
8 mg/ml Colourless Yellow (++)
16 mg/ml Colourless Yellow (+)
Dithiothreitol, DTT 1 mg/ml Purple powder (+++) Purple powder (++++)
Sodium hypophosphite 5 mg/ml Pink colour (+) Pink colour (++)
6.2 weak solution
Experimental solutions
Composition Consumption
Acetaminophen 0.008 gram
Codeine phosphate 0.0004 gram
Sodium chloride 0.008 gram
The disodium hydrogen phosphate dihydrate 0.0015 gram
Hydrochloric acid In right amount to pH6.0
Free radical scavenger (referring to quantitative result) in right amount
Nitrogen is an amount of Bubbling also charges into
Water for injection In right amount to 1000 milliliters
Gained solution is divided in the bottle of 10 milliliters of capacity, jumps a queue and the aluminum medicated cap adds medicated cap with the brombutyl stopper.121 ℃, sterilization after 20 minutes in autoclave, with each bottle under the condition that room temperature and 5500 ° of K actinic lights exist, perhaps storage 48 hours under dark and 70 ℃ condition.Measure any change color of preparation.
For the solution that does not contain any free radical scavenger with contain the solution of 0.5 mg/ml cysteine hydrochloride as free radical scavenger, after the autoclave sterilization, adopt high effective liquid chromatography for measuring acetaminophen and codeine immediately, and compare with the solution of sterilizing without autoclave.
The outward appearance scoring of solution
Free radical scavenger Concentration The outward appearance of solution behind the chance light Outward appearance at 70 ℃ of solution
Color The degree of depth Color The degree of depth
No free radical scavenger - Pink colour (+) Pink colour (+)
Sodium sulfite 0.295 mg/ml Colourless Colourless
Dithiothreitol, DTT 0.5 mg/ml Colourless Colourless
Monothioglycerol 0.5 mg/ml Lycoperdon polymorphum Vitt Lycoperdon polymorphum Vitt
Reduced glutathione 2.0 mg/ml Colourless Colourless
N-acetylcystein 2.0 mg/ml Lycoperdon polymorphum Vitt (+) Lycoperdon polymorphum Vitt (+)
Cysteine hydrochloride 0.05 mg/ml Colourless Pink colour (+)
0.1 mg/ml Colourless Colourless
0.25 mg/ml Colourless Colourless
0.5 mg/ml Colourless Colourless
0.75 mg/ml Colourless Colourless
1.0 mg/ml Colourless Colourless
2.0 mg/ml Colourless Colourless
5.0 mg/ml Colourless Colourless
The analysis result of acetaminophen and codeine
Experimental solutions Component analysis Unpasteurized solution After the sterilization
The solution that does not add free radical scavenger The acetaminophen codeine 0.0078 grams per milliliter 0.00043 grams per milliliter 0.0077 grams per milliliter 0.00042 grams per milliliter
The solution that contains 0.5 mg/ml cysteine hydrochloride The acetaminophen codeine 0.0082 grams per milliliter 0.00042 grams per milliliter 0.0081 grams per milliliter 0.00042 grams per milliliter
It should be noted that on the one hand to lack change color, on the other hand, behind heat treated sterilization, can preserve active component admirably.
Example VII A
Biological tolerance to preparation
7.1 blood toleration
Experimental solutions
Composition Consumption
Acetaminophen 0.160 gram
Propylene glycol 0.270 milliliter
PEG?400 0.360 milliliter
Nitrogen is an amount of Bubbling also charges into
Water for injection In right amount to 1000 milliliters
The pH value of regulator solution not.Apparent pH is 7.6, and corresponding actual pH is 6.5.
Isopyknic people's whole blood is cultivated with solution with research.Draw 2 milliliters of culture fluid with 10 minutes intervals, and with the rotating speed of 5000rpm centrifugal 5 minutes.Dilute 100 microlitre supernatant with 1 ml distilled water.Make blank with water, be determined at absorbing wavelength 540nm place, hemoglobin peak, the absorbance of this solution.
This research is relatively carried out negative control (normal saline) and positive control (pure water for injection).
The result
The absorbance of each solution of measuring after different time is cultivated is as shown in the table:
Solution 0 o'clock 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes
Pure water for injection 2.23 ?2.52 ?2.30 ?2.37 ?2.38 ?2.33 ?2.36
Normal saline 0.04 ?0.05 ?0.05 ?0.05 ?0.04 ?0.05 ?0.04
Experimental solutions 0.09 ?0.19 ?0.27 ?0.25 ?0.24 ?0.24 ?0.25
Do not detect haemolysis.
7.2 muscle toleration
Experimental solutions
Composition Consumption
Acetaminophen 0.160 gram
Propylene glycol 0.270 milliliter
PEG?400 0.360 milliliter
Nitrogen is an amount of Bubbling also charges into
Water for injection In right amount to 1000 milliliters
The pH value of regulator solution not.Apparent pH is 7.6.
Be to inject urethanes (2 milliliters of/kilogram 50% aqueous solutions) in the Sprague-Dawley rat peritoneum of 260-450 gram to make its anesthesia to body weight.Dissect extensor digitorum longus from its right rear leg and left back lower limb, and be placed in the buffering substrate with following composition:
Composition Consumption
Sodium chloride 6.8 gram
Potassium chloride 0.4 gram
Dextrose 1.0 gram
Sodium bicarbonate 2.2 gram
Phenol red (sodium salt) 0.005 gram
Distilled water in right amount extremely 1 liter
Hydrochloric acid 1N in right amount extremely pH7.4
Muscle is temporarily fixed onboard, and kept its position by tendon.Hamilton702 injector to inject 15 microlitre experimental product with 25 microlitre capacity make muscle pass through screen cloth then, and are immersed in 37 ℃ the buffer, and bubbling feeds carbogen in incubation.With 30 minutes interval,, the muscle immigration is contained in the pipe of fresh buffer at 37 ℃.This method repeats 4 times.Measure the creatine kinase activity of the buffer of so cultivating.
This research is parallel in the following manner to be carried out:
-muscle is not injected (blank)
-only acupuncture (acupuncture and do not inject product)
-normal saline
-Triton X-100 solution (negative control)
-No. 20 solution
-No. 20 solution+acetaminophen 160 mg/ml.
With Hitachi's 704 type analysis instrument, be used in combination the test kit of selling with efficient Enzyline CK NAC 10 (Biomerieux) trade name, measure creatine kinase activity.
The result
The creatine kinase activity (IU/I) of solution is shown in the following table as each after different culture periods:
Experimental solutions 30 minutes 60 minutes 90 minutes 120 minutes Amount to
Muscle itself 23±6 24±12 15±7 13±5 75
Only acupuncture 35±6 33±10 20±4 18±7 106
Normal saline 30±6 10±12 17±5 23±4 100
Triton-X 1802±2114 1716±978 155±89 289±251 14962
No. 20 solution (excipient) 71±24 89±40 39±27 62±39 261
No. 20 solution+acetaminophen 141±40 150±60 68±63 34±24 393
Use the present composition not find downright bad phenomenon, because between the result of experimental solutions and excipient solution, there is not significant difference.

Claims (21)

1. the new stable liquid preparation in aqueous solvent based on acetaminophen, wherein acetaminophen is dissolved in the aqueous solvent of the deoxidation by blasting the water-insoluble noble gas, and this aqueous solvent is to contain water and polyol, or the mixture of water-soluble alcohol and buffer agent, and this liquid preparation also comprises at least a free-radical antagonists or scavenger, and by buffer agent the pH value of aqueous solvent is adjusted to 4-8.
2. claim 1 is new stable to pounce on the liquid preparation of breath burning pain, wherein with buffer agent pH value is adjusted to be about 6.
3. claim 1 is new stable to pounce on the liquid preparation of breath burning pain, and wherein free radical scavenger is selected from ascorbic acid derivates, has the organic compound and the polyol of at least one thiol functional group.
4. claim 3 is new stable to pounce on the liquid preparation of breath burning pain, wherein ascorbic acid derivates be selected from D-ascorbic acid, L-ascorbic acid, ascorbic acid alkali metal salt, ascorbic acid alkali salt and dissolve in the acid ascorbyl ester of water-bearing media.
5. claim 3 is new stable to pounce on the liquid preparation of breath burning pain, and the organic compound that wherein has thiol functional group is selected from aliphatic series or the alicyclic compound that has one or more thiol.
6. claim 5 is new stable to pounce on the liquid preparation of breath burning pain, wherein has chemical compound selected from mercapto acetic acid, thiolactic acid, dithiothreitol, DTT, reduced glutathione, thiourea, α-thioglycerol, cysteine, acetylcysteine and the sulfydryl ethyl sulfonic acid of thiol functional group.
7. claim 3 is new stable to pounce on the liquid preparation of breath burning pain, and wherein polyol is the aliphatic polyol that contains 2-10 carbon atom.
8. claim 7 is new stable to pounce on the liquid preparation of breath burning pain, and wherein polyol is selected from mannitol, sorbitol, inositol and glucose.
9. claim 7 is new stable to pounce on the liquid preparation of breath burning pain, and wherein polyol is a glycerol.
10. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also contains at least a chelating agen.
11. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9, wherein the concentration of the acetaminophen of weak solution is the 2-50 mg/ml.
12. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9, wherein the concentration of the acetaminophen of concentrated solution is the 60-350 mg/ml.
13. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 wherein also comprises the morphine class analgesic that acts on the central nervous system.
14. claim 13 is new stable to pounce on the liquid preparation of breath burning pain, wherein morphine class analgesic is natural, semi-synthetic or synthetic morphine derivatives, or piperidine derivative.
15. claim 14 is new stable to pounce on the liquid preparation of breath burning pain, wherein the content of morphine class analgesic is: if morphine then is the 0.05%-5% of acetaminophen, if codeine then is the 0.2-2.5% of acetaminophen.
16. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also comprises phenylacetic acid class antibiotic medicine.
17. claim 16 is new stable to pounce on the liquid preparation of breath burning pain, wherein the antibiotic medicine is a ketoprofen.
18. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also comprises Bendectin.
19. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also comprises town's epilepsy medicine.
20. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also comprises corticosteroid.
21. each new stable to pounce on the liquid preparation of breath burning pain of claim 1-9 also comprises tricyclics.
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